In North America, lung cancer is the leading cancer in males and the leading cause of cancer deaths in both males and females1. Non-small cell lung cancer (NSCLC) represents 80% of all lung cancers and has an overall 5-year survival rate of only 16%1. Tumor stage is the primary determinant for treatment selection for NSCLC patients. Recent clinical trials have led to the adoption of adjuvant cisplatin-based chemotherapy in early stage NSCLC patients (Stages IB-IIIA).
The 5-year survival advantage conferred by adjuvant chemotherapy in recent trials are 4% in the International Adjuvant Lung Trial (IALT) involving 1,867 stage I-III patients2, 15% in the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) BR.10 Trial involving 483 stage IB-II patients3, and 9% in the Adjuvant Navelbine International Trialist Association (ANITA) trial involving 840 stage IB-IIIA patients4. Pre-planned stratification analysis in the later two trials showed no significant survival benefit for stage IB patients3,4. This was also demonstrated in the Cancer and Leukemia Group (CALGB) Trial 9633 that tested the benefit of chemotherapy on 344 stage IB patients receiving carboplatin and paclitaxel or observation5. Although initially presented in 2004 as a positive trial, recent survival analyses show no significant survival advantage with chemotherapy for either disease-free survival (HR=0.80, p=0.065) or overall survival (HR=0.83, p=0.12)5. In an attempt to draw an overall conclusion regarding the effectiveness of adjuvant cisplatin-based chemotherapy, the Lung Adjuvant Cisplatin Evaluation (LACE) meta-analysis was conducted which synthesized information from the 5 largest published, cisplatin-based trials that did not administer concurrent thoracic radiation [Adjuvant Lung Project Italy (ALPI)7, Big Lung Trial (BLT)8, IALT2, BR.103, and ANITA9]. The study found a 5.3% absolute survival advantage at 5-year (HR=0.89, 95% Cl 0.82-0.96, p=0.004). However, stratified analysis by stage showed that the stage IB patients did not benefit significantly from cisplatin treatment (HR=0.92, 95% Cl 0.78-1.10). Moreover, a detriment for chemotherapy was suggested in stage IA patients (HR=1.41, 95% Cl 0.96-2.09)6. Therefore, the current standard of treatment for patients with stage I NSCLC remains surgical resection alone. However, 30 to 40 percent of these stage I patients are expected to relapse after the initial surgery10,11, indicating that a subgroup of these patients might benefit from adjuvant chemotherapy.
The lack of consistent prognostic molecular markers for early stage NSCLC patients led to attempts to identify novel gene expression signatures using genome wide microarray platforms. Such multi-gene signatures might be stronger than individual genes to predict poor prognosis and poor prognostic patients could potentially benefit from adjuvant therapies. Previous microarray studies have identified prognostic signatures that demonstrated minimal overlaps in the gene sets.12-20 While only one of the early studies involved secondary signature validation in independent datasets12, all recently reported signatures were tested for validation13-16,20. Nevertheless, lack of direct overlaps between signatures remains. One of the potential confounding factors is that signatures were derived from patients operated at single institutions, which may introduce biases.